The melanocortin receptors (MC-receptors) belong to the class of G-protein coupled receptors which are all built from a single polypeptide forming seven transmembrane domains. The melanocortin receptors are linked to a variety of physiological actions that are thought to be mediated by distinct subtypes of the MC-receptors. The melanocortin receptor's signaling is mainly mediated via cAMP but also other signal transduction pathways are known. To date, five receptors types, termed MC1-R, MC2-R, MC3-R, MC4-R and MC5-R, have been described. Melanocortin-1 receptors (MC1-R) are expressed on normal human melanocytes and melanoma cells, melanocortin-2 receptors (MC2-R) for ACTH (adrenocorticotropin) are expressed in cells of the adrenal gland, melanocortin-3 and melanocortin-4 receptors (MC3-R and MC4-R) are expressed primarily in cells in the hypothalamus, mid-brain and brainstem, and melanocortin-5 receptors (MC5-R) are expressed in a wide distribution of peripheral tissues.
In general, compounds specific for MC3-R, MC4-R or MC5-R are believed to be useful in regulation of energy homeostasis, including use as agents for attenuating food intake and body weight gain, in treatment of cachexia, in treatment of anorexia, as a weight gain aid, in treatment of obesity, and in other treatment of other food intake and metabolism-related purposes. Compounds specific for MC3-R and MC4-R, among other melanocortin receptors, can be used to regulate blood pressure, heart rate and other neurophysiologic parameters. MC4-R antagonists can be used in the treatment of anxiety/depression, pain, and addiction to drugs of abuse. However, in many cases, it is not entirely clear which of the subtypes is responsible for the effect. Melanocyte-stimulating hormones (referred to as MSH) are known agonist of the melanocortin receptors. MSH are a class of peptide hormones including ACTH, α-MSH, β-MSH and γ-MSH. MSHs are believed to affect many different processes such as motivation, learning, memory, behavior (including feeding and sexual), inflammation (including immunostimulatory and immunosuppressive), body temperature, pain perception, blood pressure, heart rate, vascular tone, brain blood flow, trophic effects in different organs, nerve growth, placental development, endocrine and exocrine functions, aldosterone synthesis and release, thyroxin release, spermatogenesis, ovarian weight, prolactin and FSH secretion, effects on other organs, uterine bleeding in women, sebum and pheromone secretion, blood glucose levels, intrauterine fetal growth, as well as other events surrounding parturition and natriuresis as well as inducing natriuresis. MC4-R agonists are believed to be useful for treating sexual dysfunction, for decreasing the body weight and for treatment of depression and related disorders.
There remains a significant need for pharmaceutical compositions and methods of orally administering pharmaceutical compositions comprising peptide-based melanocortin receptor agonists to treat a various melanocortin receptor-mediated diseases. More particularly, there is significant need for pharmaceutical compositions and methods of orally administering pharmaceutical compositions comprising peptide-based melanocortin receptor agonists to treat various melanocortin receptor-mediated diseases with substantially reduced incidence of undesirable side effects.